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  • Title: An adenosine analogue, IB-MECA, down-regulates estrogen receptor alpha and suppresses human breast cancer cell proliferation.
    Author: Lu J, Pierron A, Ravid K.
    Journal: Cancer Res; 2003 Oct 01; 63(19):6413-23. PubMed ID: 14559831.
    Abstract:
    Adenosine, a natural metabolite, plays important roles in several physiological and pathological processes, including modulation of cellular proliferation. Here, we report that among different adenosine analogues tested, micromolar concentrations of the A(3) adenosine receptor (A(3)AR)-selective agonist N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA) completely inhibited the growth of the human breast cancer cell lines MCF-7 and ZR-75 while inducing apoptosis in T47D and Hs578T cells, which do not express A(3)AR mRNA. In MCF-7 cells, A(3)AR overexpression did not increase the sensitivity to drug treatment and an A(3)AR antagonist did not abolish IB-MECA effect. In search for mechanisms of the effect of this ligand, we found that in estrogen receptor alpha (ERalpha)-positive cells, IB-MECA rapidly down-regulated ERalpha at mRNA and protein levels and consequently at the transcriptional activity level. Moreover, overexpression of ERalpha in MCF-7 cells alleviated the proliferation inhibition induced by IB-MECA. The inhibitory effects on cell growth and to some extent on ERalpha were mimicked by 2-chloro-adenosine >3'-deoxyadenosine> adenosine but not by a variety of other ligands. Our studies indicate that IB-MECA can down-regulate ERalpha and inhibit proliferation or induce apoptosis in different breast cancer cell types and raise the possibility of using this and related compounds in breast cancer treatment.
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